A number of autoimmune diseases show gender differences in susceptibility and severity. Multiple Sclerosis afflicts females at nearly twice the frequency as males; however, males tend to have a more severe disease profile and mortality. In our murine model of demyelination/remyelination that show features similar to MS, we find male mice that are chronically exposed to a neurointoxicant, cuprizone, undergo episodic demyelination/remyelination in the central nervous system. After a third episode of demyelination, male mice show grand mal seizures and die whereas females, although undergo similar episodic demyelination/remyelination, remain viable longer. This proposal investigates the role of estrogen, estrogen receptors and growth factors that may account for gender differences in seizures and demyelinating disease. We will study a plausible mechanism for the action of estrogen, test in vivo whether estrogen and IGF-1 can alter disease progression in male and female mice, and the role of estrogen receptors in gender differences. Our hope is to understand the interplay of these factors and elucidate mechanisms that may alter or ameliorate CNS demyelinating disease in both genders.